Leptin suppresses food intake via its biological actions on the central nervous system. SH2-B, a JAK2 binding protein, is expressed in leptin-sensitive neurons within the hypothalamus, and promotes leptin signaling in cultured cells. SH2-B deficient mice develop hyperphagia, leptin resistance, and obesity, confirming that SH2-B is a key mediator of leptin action and energy balance in vivo. This proposal will address the role of SH2-B in AgRP neurons, one population of leptin sensitive neurons in the hypothalamus implicated in the control of food intake. A conditional loss-of-function approach (Cre/LoxP) will be used to test the central hypothesis that SH2-B regulates energy balance predominantly by regulating leptin sensitivity in AgRP neurons within the arcuate nucleus of the hypothalamus. The extent to which SH2-B directly regulates leptin signaling in AgRP neurons will be determined (aim 1), and the relative contribution of SH2-B in AgRP neurons to the intrinsic regulation of energy balance and leptin sensitivity (aim 2) will be addressed. These studies will provide considerable insight into the mechanisms by which SH2-B promotes leptin sensitivity and contributes to the central regulation of energy homeostasis. [unreadable] [unreadable] [unreadable]